Benzoylamino substituted 1-benzoyl-piperidines

ABSTRACT

AMINOPIPERIDINE DERIVATIVES OF THE FORMULA   1-((R&#39;&#39;1,R&#39;&#39;2-PHENYL)-CO-),((R1,R2,R3-PHENYL)-CO-NH-)   PIPERIDINE   WHEREIN SUBSTITUTED BENZAMIDE RADICAL ATTACHES TO 2,3,4POSITIONS IN THE PIPERIDINE NUCLEUS, AND EACH R1, R2 R3 IS HYDROGEN OR LOWER ALKOXY WHICH CAN BE CHANGED INDEPENDENTLY. R&#39;&#39;1, R&#39;&#39;2 OF SUBSTITUTED BENZOYL RADICAL WHICH ATTACHES TO NITROGEN OR PIPERIDINE NUCLEUS ARE HYDROGEN OR AMINO RADICAL AND AT LEAST ONE OF R&#39;&#39;1, R&#39;&#39;2 INDICATES AMINO RADICAL. THE NEW COMPOUNDS EXHIBITS THREPEUTIC EFFECT FOR EXPERIMENTAL GASTRIC ULCER.

United States Patent ()flice 3,647,805 Patented Mar. 7, 1972 ABSTRACT OFTHE DISCLOSURE AminOpiperidine derivatives of the formula whereinsubstituted benzamide radical attaches to 2,3,4- positions in thepiperidine nucleus, and each R R R is hydrogen or lower alkoxy which canbe changed independently. R' 'R' of substituted benzoyl radical whichattaches to nitrogen or piperidine nucleus are hydrogen or amino radicaland at least one of R indicates amino radical.

The new compounds exhibit therapeutic effect for experimental gastriculcer.

This invention relates to aminopiperidine derivatives expressed by thefollowing general formula:

wherein substituted benzamide radical attaches to 2,3,4- positions inthe piperidine nucleus, and each R R R is hydrogen or lower alkoxy whichcan be changed independently. R' R';; of substituted benzoyl radicalwhich attaches to nitrogen of piperidine nucleus are hydrogen or aminoradical and at least one of R R indicates amino radical.

The compounds of this invention can be prepared according to thefollowing three process schemes:

PROCESS I N Ra (III) wherein R R R are as previously defined and theposition of the substituted benzamide radical in the pyridine orpiperidine is as previously defined.

The compound (III) of this invention has not yet been described in theliterature.

The compound (III) can be prepared by the hydrogenation reaction of (II)PROCESS II R1 R! Q @v- 11; R3 R"g (L NH C 0- R2 (111) N J: RI!l Qwherein R R R of (III) are as previously defined and R";, of (IV) arehydrogen or nitro radical and at least one of R" R indicates nitroradical and the X represents halogen atom.

The compound (V) of this invention has not yet been described in theliterature.

The compound (V) can be prepared by the reaction of (III) with (IV) inthe presence of weak alkali.

wherein R R' R R";, R":, R' R' of (V) and (I) and the position ofsubstituted benzamide radical are as previously defined.

The compound (I) of this invention has not yet been described in theliterature.

The compound (I) can be prepared by the hydrogenation reaction of (V).

In the process I, pyridine ring of (II) was reduced in ethanolcontaining dilute hydrochloric acid by the use of a catalytic amount of5% palladium-carbon at an initial pressure of 35-45 atm. of hydrogen at60-80 C. or it was reduced in ethanol containing dilute hydrochloricacid by the use of platinum oxide catalyst at a hydrogen pressure of 6atm. at room temperature.

In the process II, the solvents such as acetonitrile, chloroform orwater are suitable solvents. Suitable weaker alkalis such as pyridine,triethylamine sodium bicarbonate, or potassium carbonate must be used.

In the process III, the reduction of (I) shows a method of hydrogenatingof (V) in methanol or ethanol in the presence of reducing agents.Suitable reducing agent are platinum oxide, palladium-carbon, Raney-Nicatalyst and general reducing agent such as zinc and acetic acid.

Through new investigation of gastric ulcer, this inven tion of ulcerremedies was produced. Drugs for gastric ulcer, gastric secretioninhibitory drugs or central nervous system depressants, which resultedfrom evaluations of protective tests on Shays ulcer or stress ulceretc., have been considered to have curative activity on chronic ulcers.But gastric secretion inhibitory drugs or central nervous systemdepressants are not appropriate for ulcer remedies of human gastriculcer, for there are histological differences between chronic ulcer ofhuman beings and acute ulcers in experimental gastric ulcers.

Therefore, we produced the experimental gastric ulcers by aclamping-cortisone method (Umehara, et al. J. Therap. 47, 397 (1965))which microscopically revealed ulcers. From the following days 6 ulcerdays) of the last treatment of cortisone acetate, test compounds weread-' Ma gi As the results of the screening test, we found the compoundsthat possessed curative activity for the said ulcers in aminopiperidinederivatives. These results were summerized in Table I, and therepresentative test compound,

for example, 1 (p-aminobenzoyl) 3-(3,4,5-trimethoxyquite a resemblanceto those of human gastric ulcers and benzamide)-piperidine (Example 12)was compared with to those experimental gastric ulcers histologicallyevaluthe positive control, oxymetholone, and the results were ated thetest compounds as the object of healing process. summerized in Table II.

The gastric walls of white male rats were clamped for 1(p-aminobenzoyl)-3-(3,4,5-trimethoxybenzamide)- 24 hours. Animals weregiven 7 mg. of cortisone acetate piperidine was better than oxymetholoneon the degree of per 100 g. of body weight for 7 days after theoperation. the healing, regenerated mucosa and collagenous fibers Bythese procedures, animals developed chronic gastric proliferation.

TABLE I NHR i R D/fisei lgagspf R R d 'y notice 8 135. 5: Compound No.:

OCH: 7.5 R0 20 l -C0 NH: R0 20 -CO -OGII;

OCH3

2 Same as above. 20 P4); 20

-coocm 3-..:-:....... OCH; 20 P.o. 21

I -OO -Co -0 CH3 4. Same as above.-.-... NH; 20 P.o. 20

IFIHCO- Ulcer index (percent) A At/Ac B Bt/Be C Ct/Cc T.C. T.Ct/'I.Cc

NOTE .A=healing index; B=regenerated mucosa index; C=degree ofcollagenous fibers 0 T.C of test comoound/T.C. of control.

TABLE II Dose,! Ulcer index (percent) e-l J Treatment day Route A At/AoB Bt/Bc C Ct/Ce T.C T.Gt/T.Cc

Oxyrnetholone 53.0 2. 1 60. O 1. 2 34.0 1. 9 49.0 1. 7 Control 2 5 6. 218. 0 29. 6 Oxylnetholone 54.0 2. 2 61.0 1. 2 35. 0 1.5 50.0 1. 7Control P.o. 24. B 45. 0 20.0 29. 6 l-(p-arninobenzoyl)-3-(3,4,5-trl- 7.5 R0. 59. 5 2. 4 63. 2 1. 3 39.0 2. 2 52. 1. 8

methoxybenzamide) piperidine. 60 P.o. 59. 6 2. 4 66. 8 1. 4 42.0 2. 356. 1 1. 9 Control P.O. 24. 5 46. 2 18. 0 29. 6

NOTE At/AQ=A of test compound/A of control; Bt/Bc=B of test compound/Bof control; Ct/Cc=C of test compound/O of control; T.Ct/T. nous fibersproliferation; T.C=total healing index.

EXAMPLE 1 3-(3,4,5-trimethoxybenzamide)piperidine hydrochloride 'Asolution of 3-(3,4,5-trimethoxybenzamide)pyridine (4g) in ethanol (30ml.) containing water (9 ml.) and 36% HCl (1.4 g.) was hydrogenated inthe presence of platinum oxide (0.1 g.) at 4050 C. and at an initialpressure of 6 atm. Uptake of hydrogen was complete in less than 2 hr.The mixture was cooled and filtered from the catalyst. After removal ofthe solvent, the crude product was collected. Recrystalization fromacetonitrile gave 3-(3,4,5 trimethoxybenzamide)piperidine hydrochlorideas colorless needles, M.P. 206209 0., yield Analysis.Calcd. for C H O N-HCL1/2H O (percent): C, 53.02; H, 7.12; N, 8.24. Found (percent): C,53.24; H, 7.09; N, 8.09.

EXAMPLE 2 ethoxybenzamide)piperidine hydrochloride The compound wasobtained by following the same process as in Example 1.Recrystallization from acetonitrile yielded 80% of needles, M.P. 147-150C.

Analysis.Calcd. for C H O N -HCl (percent): N, 8.46. Found (percent): N,8.38.

EXAMPLE 3 3-(3,4,5-trimethoxybenzamide)piperidine A solution of3-(3,4,5-trimethoxybenzamide) pyridine (3 g.) in ethanol ml.) containingwater (9 ml.) and 36% HCl (1.1 g.) was hydrogenated in the presence of5% palladium-carbon (l g.) at 60'80 C. and at an initial pressure of -45atm. Uptake of hydrogen was complete in 2 hr. The mixture was cooled andfiltered from the catalyst. After removal of the solvent, the crudeproduct was collected. After being neutralized by NaI-ICOrecrystallization from acetonitrile gave 3-(3,4,5-trimethoxybenzamide)piperidine as colorless needles, M.P. l7918l.5 0., yield 90%.

Analysis.- Calcd. for C H O N (percent): C, 61.20; H, 7.53; N, 9.52.Found (percent): C, 61.63; H, 7.40;

2-(3,4,5-trim Cc=T.C of test compound/T.O of control; A=healing index; B=regenerated mucosa index; C=degree of college- EXAMPDE 43-(p-methoxybenzamide)piperidine hydrochloride The compound is obtainedby following the same process as in Example 1 or Example 3.Recrystallization from methanol yielded of amorphous powder, M.P. 234-236 C.

Analysis.Calcd. for C H O N -HCl (percent): N. 10.34. Found (percent):N, 10.16.

EXAMPLE 5 3- 3 ,5 -dimethoxybenzamide piperidine hydro chloride Thecompound was obtained by following the same process as in Example 1 or3. Recrystallization from methanol yielded 88% of amorphous powder, M.P.224- 226.5" C.

Analysis.Calcd. for c,,H, 0,N -Hc1 (percent): C, 55.90; H, 7.03; 'N,9.31. Found (percent): C, 55.98: H. 7.02; N, 9.34.

EXAMPLE 6 3 (2,3 -dimethoxybenzamide piperidine hydrochloride Thecompound was obtained by following the same process as in Example 1 or3. Recrystallization from acetonitrile yielded 90% of needles, M.P.215-216.5 C.

Analysis.Calcd. for C H O N -HCl (percent): C, 55.90; H, 7.03; N, 9.31.Found (percent): C, 55.90; H,

EXAMPLE 7 l (p-nitrobenzoyl) -3 3 ,4,5-trimethoxybenzamide) piperidine Asolution of p-nitrobenzoylchloride (5.6 g.) in acetonitrile (3 ml.) wasadded gradually to a solution of 3- 3,4,5-trimethoxybenzarnide)piperidine hydrochloride (9.9 g.) in water (40ml.) containing NaHCO (6.3 g.) with vigorous stirring under cooling withan ice-bath. During the addition, the crude product separated out. Afterstirring 1 hr. at room temperature, the product was filtered, and washedwith water, and recrystallized from isopropyl alcohol to givel-(p-nitrobenzoyl) 3 (3,4,5-trimethoxybenzamide)piperidine as colorlessneedles. M.P. 121-124" C.; yield 80%.

7 Analysis.alcd. for C22H2507N3'H20 (percent): C, 57.26; H, 5.96; N,9.11. Found (percent): C, 57.21; H, 5.90; N, 9.10.

EXAMPLE 8 1 (m-nitrobenzoyl) -3 (3 ,4,5-trimethoxybenzamide) piperidineThe compound is obtained by following the same process as in Example 7.Recrystallization from isopropyl alcohol and water yielded 98% ofneedles, M.P. 97-100 C.

Analysis.Calcd. for C H O N -H O (percent): C, 57.26; H, 5.90; N, 9.11.Found (percent): C, 57.61; H, 6.14; N, 9.18.

EXAMPLE 9 1- (p-nitrobenzoyl)-3-(p-methoxybenzamide) piperidine Thecompound was obtained by following the same process as in Example 7.Recrystallization from acetonitrile yielded 66% of needles, M.P. 186-188C.

Analysis.-Calc. for C H O N (percent): C, 62.65; H, 5.52; N, 10.96.Found (percent): C, 62.40; H, 5.59; N, 11.31.

EXAMPLE 10 1- (p-nitrobenzoyl)-2-(3,4,5-trimethoxybenzamide) piperidineThe compound was obtained by following the same process as in Example 7.Recrystallization from acetonitrile yielded 70% of plates, M.P. 205-208"C.

Analysis.Calc. for C22H25O7N3 (percent): C, 59.58; H, 5.68; N, 9.48.Found (percent): C, 59.79; H, 5.85; N, 9.77.

EXAMPLE 1 1 l-(m-nitrobenzoyl) -3-(p-methoxybenzamide) piperidine Thecompound was obtained by following the same process as in Example 7.Recrystallization from acetonitrile yielded 61.5% of needles, M.P.128-13l C.

Analysis-Cale. for C H O N (percent): C, 54.09; H, 4.95; N, 11.47. Found(percent): C, 53.59; H, 5.16; N, 11.14.

EXAMPLE 12 l-(p-nitrobenzoyl)-4-(3,4,5-trimethoxybenzamide) piperidineThe compound was obtained by following the same process as in Example 7.Recrystallization from acetonitrile yielded 79% of needles, M.P. 160-162C.

Analysis.-Calc. for C H 0 N -H O (percent): C,

57.26; H, 5.90. Found (percent): C, 57.64; H, 5.79.

EXAMPLE 13 1-(p-aminobenzoyl)-3-(3,4,5-trimethoxybenzamide) piperidine 8EXAMPLE 14 1-(p-aminobenzoyl)-3-(3,4,5-trimethoxybenzamide) piperidine Asolution of 1-(p-nitrobenzoyl)-3-(3,4,5-trimethoxybenzamide)piperidine(5 g.) in ethanol (30 ml.) was hydrogenated in the presence of Raney-Ni(5 'g.) at 40-70 C. and at an initial pressure of 47 atm. The reactionmixture was treated by the method of Example 13 to give colorlessneedles, M.P. 125-127" C.

EXAMPLE 15 ;1-(p-aminobenzoyl)3-(3,4,5-trimethoxybenzaimde) piperidine Asolution of 1-(p-nitrobenzoyl)-3-(3,4,5-trimethoxybenzamide)piperidine(5 g.) in ethanol ml.) was hydrogenated in the presence of 10%palladium-carbon (0.5 g.) at atmospheric pressure and room temperature.The reaction mixture was treated by the method of Example 13 to givecolorless needles, M.P. -127" C.

EXAMPLE 16 l-(p-aminobenzoyl)-2-(3,4,5-trimethoxybenzamide) piperidineThe compound was obtained by following the same process as in Examples13-15. Recrystallization from dimethylformamide and acetonitrile yielded77.2% of amorphous powder, M.P. 2l4-2l6 C.

Analysis.Calc. 01 C22H2705N3'H20 (PGI'CEHII): N, 10.16. Found (percent):10.42.

EXAMPLE 17 l-(m-aminobenzoyl)-3-(3,4,5-trimethoxybenzamide) piperidineThe compound was obtained by following the same process as in Examples13-15. Recrystallization from dimethylformamide and water yielded 82% ofplates, M.P. 219-220.5 C.

Analysis.-Calc. for C H O N (percent): C, 63.90; I-l), 62.58; N, 10.16.Found (percent): C, 63.87; H, 6.60; N, 1 .1

EXAMPLE 18 1-(3,S-diaminobenzoyl)-3-(3,4,5-trimethoxybenzamide)piperidine The compound was obtained by following the same process as inExamples 13-15. Recrystallization from isopropyl alcohol yielded 72% ofamorphous powder, M.P. 164-167 C.

Analysis-Cale. for C H O N -H O (percent): C, 59.18; H, 6.77; N, 12.55.Found (percent): C, 59.42; H, 6.66; N, 12.63.

EXAMPLE 19 l-(o-aminobenzoyl)-3-(3,4,5-trimethoxybenzamide) piperidineThe compound was obtained by following the same process as in Examples13-15. Recrystallization from dimethylformamide and water yielded 71.5%of amorphous powder, M.P. 172-175 C.

Analysis.Calc. for C22H27O5N3 (percent): C, 63.90; H, 6.58; N, 10.16.Found (percent): C, 63.77; H, 6.66; N, 9.94.

EXAMPLE 20 1- (p-aminobenzoyl) -3- (p-methoxybenzamide pip eridine Thecompound was obtained by following the same process as in Examples13-15. Recrystallization from acetonitrile yielded 70% of plates, M.P.225-2275 C.

Analysis.Calc. for cQoHfl3o8Na' 2HQO (percent): C, 66.28; H, 6.68. Found(percent): C, 66.373111, 6.75.

9 EXAMPLE- 21 l-(p-aminobenzoyl)-3-(3,S-dimethoxybenzamide) piperidineThe compound was obtained by following the same 5 process as in Examples13-15. Recrystallization from acetonitrile yielded 74% of plates, M.P.197.5-200" C.

Analysis.-Calc. for C H O N (percent): C, 65.78; H, 6.57; N, 10.96.Found (percent): C, 65.64; H, 6.47;

EXAMPLE 22 1-(p-aminobenzoyD-3-(3,4,5-trimethoxybenzamide) piperidinehydrochloride The compound was obtained by following the same process asin Examples 13-15. Recrystallization from ethanol and isopropyl alcoholyielded 88% of needles, M.P. 185-187 C.

Analysis.--Calc. for c H O N -HCl- /zH o (percent): C, 57.57; H, 6.26;N, 9.15. Found (percent): C, 57.43; H, 6.37; N, 8.91.

EXAMPLE 23 l benzoyl-3-(3,4,S-trimethoxybenzamide)piperidine Thecompound was obtained by following the same process as in Examples13-15. Recrystallization from acetonitrile yielded 58% of prisms, M.P.193-196 C.

Analysis.Calc. for C H 0 N (percent): C, 66.31; H, 6.58; N, 7.03. Found(percent): C, 66.30; H, 6.59; N, 7.09.

EXAMPLE 24 wherein R R R and the position of substituted benzamideradical are as previously defined and R" R" are hydrogen or nitroradical and at least one of R R" indicates nitro radical.

2. 1 (p-nitrobenzoyl)-3-(3,4,5-trimethoxybenzamide) piperidine.

3. 1 (m-nitrobenzoyl)-3-(3,4,S-trimethoXy-benzamide) piperidine.

4. 1 (p-nitrobenzoyl)-3-(p-methoxybenzamide)piperidine.

5. 1 (p-nitrobenzoyl)-2-(3,4,5-trimethoxybenzamide) piperidine.

6. 1 (m-nitrobenzoyl) 3 (p-methoxybenzamide) piperidine.

7. l (p-nitrobenzoyl)-4-(3,4,5-trimethoxybenzamide) piperidine.

8. A compound of the formula:

wherein R R R and the position of substituted benzamide radical are aspreviously defined and R' R;; are hydrogen or amino radical and at leastone of R' R; indicates amino radical.

9. 1 (p-aminobenzoyl) 3 (3,4,5-trimethoxybenzamide)piperidine.

10. 1 (p-aminobenzoyl) 2 (3,4,5-trimethoxybenzamide)piperidine.

11. 1 (m-aminobenzoyl) 3 (3,4,5-trimethoxybenzamide)piperidine.

12. 1 (3,5-diaminobenzoyl)-3-(3,4,5-trimethoxybenz amide)piperidine.

13. 1 (p-aminobenzoyl)-3-(3,5-dimethoxybenzamide) piperidine.

14. 1 (p-aminobcnzoyl) 3 (p-methoxybenzamide) piperidine.

15. 1 (p-aminobenzoyl) 3 (3,4,5-trimethoxybenzamide)piperidinehydrochloride.

16. 1 (p-aminobenzoyl 4 (3,4,5-trimethoxybenzamide)piperidine.

17. 3-(3,4,5-trimethoxybenzamide)piperidine.

OTHER REFERENCES Harper et al., J. Med. Chem. 7 (6), 729-32 (1964).

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl.X.R.

UNITED STATES PATENT ()FFICE CERTIFICATE OF CORRECTION 3,6u7,8o5 DatedMarch 7, 1972 Patent No.

Tsutomu IRIKURA, Kazunor-i KASUGA, and Mitsuru SEGAWA Inventor(s) ppearsin the above-identified patent It is certified that error a herebycorrected as shown below:

and that said Letters Patent are In the heading of the patent, insertthe following:

--Claims priority, application Japan,

Signed and sealed this 13 (SEAL) Attes't:

ROBERT GOTTSCHAIJK EDWARD M. FLET CHER JR Attesting Officer ICommissioner of Patents USCOMM-Dc 60375-P69 fi U.SI GOVERNMENT PRINTINGOFFICE: I969 O-366-334 F ORM PO-1050 (10-69)

